Abstract 13871: MiR-146a-induced Inhibition of Neuregulin1-ErbB4 Pathway may be Involved in Deterioration of Cardiotoxicity under Concurrent Chemotherapy with Doxorubicin and Trastuzumab.
Background: A significant increase in congestive heart failure (CHF) was reported when the anti-ErbB2 antibody trastuzumab was used in combination with the chemotherapy drug doxorubicin (Dox). Because neuregulin-1 (NRG1)-ErbB signaling is essential for maintaining adult cardiac function and several reports showed that NRG-1 ameliorates Dox-induced cardiotoxicity, we studied the effect of Dox on NRG1-ErbB signaling in the heart.
Methods and Results: We found a significant reduction in ErbB4 expression in the hearts of mice after single intra-peritoneal Dox injection (20mg/g), whereas ErbB2, which is known to form heterodimer with ErbB4, was not affected. Because the proteasome pathway was only partially involved in the reduction of ErbB4 (∼20%), we examined the involvement of miRNAs in the reduction of ErbB4 expression. We focused on the function of miR-146a, because ErbB4 has three potential miR-146a binding sites in the 3′ untranslated region (UTR) and the expression level of miR-146a was up-regulated by Dox in neonatal rat cardiac myocytes (NRCMs). We confirmed that miR-146a targets the ErbB4 3′UTR by luciferase assay. Lentivirus-mediated over-expression of miR-146a reduced ErbB4 expression in NRCMs without affecting ErbB2 expression. Over-expression of miR-146a significantly induced cell death after Dox treatment, which was comparable with siRNA against ErbB4. Re-expression of ErbB4 in miR-146a over-expressing NRCMs ameliorated Dox-induced cell death. To examine the loss of miR-146a function, we constructed ‘decoy’ genes that had tandem complementary sequences for miR-146a in the 3′UTR of a luciferase gene. When miR-146a ‘decoy’ genes were introduced into NRCMs, ErbB4 expression was up-regulated and Dox-induced cell death was significantly reduced.
Conclusions: These findings suggested that the up-regulation of miR-146a after Dox treatment is involved in acute Dox-induced cardiotoxicity by targeting ErbB4. Inhibition of both ErbB2 and ErbB4 signaling may be one of the reasons why those patients who receive concurrent therapy with Dox and trastuzumab suffer from CHF.
- © 2010 by American Heart Association, Inc.